Instrumental Variable Analyses in Pharmacoepidemiology: What Target Trials Do We Emulate?

Abstract

When leveraging observational data to estimate treatment effects, it is useful to explicitly specify the “target trial” the investigators aspire to emulate. One concern is whether a proposed analysis plan can address the realities of the differences between the available non-randomized observational study and the target trial. When large or unknown sources of unmeasured confounding are suspected, investigators might consider turning to instrumental variable (IV) methods. Of course, the interpretation and appropriateness of IV analyses need to be considered carefully. The purpose of this review is to summarize recent methodologic advancements in how epidemiologists weigh the validity of an IV analysis and to place these methodologic advancements in the context of the feasible target trial’s protocol components. There have been increased development and application of tools for sensitivity analyses, falsification strategies, and the identification of previously overlooked problems with IV analyses as applied in pharmacoepidemiology. Many of these recent insights can be seen as articulating restrictions on or tradeoffs between the types of target trials that can be validly emulated when using a classical IV analysis. Putting classical IV methods in the context of target trials underscores the importance of recent methodologic developments and, more generally, when and how an IV analysis would be appropriate. We see that some tradeoffs in defining the target trials are unavoidable, that some tradeoffs may be offset or explored via sensitivity analyses, and that this serves as a framework for scientific discourse regarding IV and non-IV results emulating potentially different trials with different tradeoffs.